| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
Adenosine (ADO) exerts potent anti-inflammatory and immunosuppressive effects. In this paper we address the possibility that these effects are partly mediated by inhibition of the secretion of IL-12, a proinflammatory cytokine and a major inducer of Th1 responses. We demonstrate that 5'-N-ethylcarboxamidoadenosine (NECA), a nonspecific ADO analogue, and 2-p-(2-carbonyl-ethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), a specific A2a receptor agonist, dose-dependently inhibited, in whole blood ex vivo and monocyte cultures, the production of human IL-12 induced by LPS and Stapholococcus aureus Cowan strain 1. However, the A1 receptor agonist 2-Chloro-N6-cyclopentyladenosine and the A3 receptor agonists N6-Benzyl-NECA and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-ß-D-ribofuranuronamide expressed only weak inhibitory effects. On the other hand, NECA and CGS-21680 dose-dependently potentiated the production of IL-10. The differential effect of these drugs on monocyte IL-12 and IL-10 production implies that these effects are mediated by A2a receptor signaling rather than by intracellular toxicity of ADO analogue’s metabolites. Moreover, CGS-21680 inhibited IL-12 production independently of endogenous IL-10 induction, because anti-IL-10 Abs failed to prevent its effect. The selective A2a antagonist 8-(3-Chlorostyryl) caffeine prevented the inhibitory effect of CGS-21680 on IL-12 production. The phosphodiesterase inhibitor Ro 20-1724 dose-dependently potentiated the inhibitory effect of CGS-21680 and, furthermore, Rp-cAMPS, a protein kinase A inhibitor, reversed the inhibitory effect of CGS-21680, implicating a cAMP/protein kinase A pathway in its action. Thus, ligand activation of A2a receptors simultaneously inhibits IL-12 and stimulates IL-10 production by human monocytes. Through this mechanism, ADO released in excess during inflammatory and ischemic conditions, or tissue injury, may contribute to selective suppression of Th1 responses and cellular immunity.
This article has been cited by other articles:
|
|
 |
|
  C. L. Lau, Y. Zhao, I. L. Kron, M. H. Stoler, V. E. Laubach, G. Ailawadi, and J. Linden The Role of Adenosine A(2A) Receptor Signaling in Bronchiolitis Obliterans. Ann. Thorac. Surg., October 1, 2009; 88(4): 1071 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. van der Putten, E. A. Zuiderwijk-Sick, L. van Straalen, E. D. de Geus, L. A. Boven, I. Kondova, A. P. IJzerman, and J. J. Bajramovic Differential Expression of Adenosine A3 Receptors Controls Adenosine A2A Receptor-Mediated Inhibition of TLR Responses in Microglia J. Immunol., June 15, 2009; 182(12): 7603 - 7612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Scheibner, S. Boodoo, S. Collins, K. E. Black, Y. Chan-Li, P. Zarek, J. D. Powell, and M. R. Horton The Adenosine A2a Receptor Inhibits Matrix-Induced Inflammation in a Novel Fashion Am. J. Respir. Cell Mol. Biol., March 1, 2009; 40(3): 251 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Lisle, L. M. Gazoni, L. G. Fernandez, A. K. Sharma, A. M. Bellizzi, G. D. Schifflett, V. E. Laubach, and I. L. Kron Inflammatory lung injury after cardiopulmonary bypass is attenuated by adenosine A(2A) receptor activation. J. Thorac. Cardiovasc. Surg., November 1, 2008; 136(5): 1280 - 1288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Huang, D. J. Moore, R. J. Ketchum, C. S. Nunemaker, B. Kovatchev, A. L. McCall, and K. L. Brayman Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation Endocr. Rev., August 1, 2008; 29(5): 603 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, F. Wu, F. Sun, and P. Huang Adenosine Promotes IL-6 Release in Airway Epithelia J. Immunol., March 15, 2008; 180(6): 4173 - 4181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ohta, D. Lukashev, E. K. Jackson, B. B. Fredholm, and M. Sitkovsky 1,3,7-Trimethylxanthine (Caffeine) May Exacerbate Acute Inflammatory Liver Injury by Weakening the Physiological Immunosuppressive Mechanism J. Immunol., December 1, 2007; 179(11): 7431 - 7438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Reutershan, R. E. Cagnina, D. Chang, J. Linden, and K. Ley Therapeutic Anti-Inflammatory Effects of Myeloid Cell Adenosine Receptor A2a Stimulation in Lipopolysaccharide-Induced Lung Injury J. Immunol., July 15, 2007; 179(2): 1254 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Polumuri, V. Y. Toshchakov, and S. N. Vogel Role of Phosphatidylinositol-3 Kinase in Transcriptional Regulation of TLR-Induced IL-12 and IL-10 by Fc{gamma} Receptor Ligation in Murine Macrophages J. Immunol., July 1, 2007; 179(1): 236 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Haschemi, O. Wagner, R. Marculescu, B. Wegiel, S. C. Robson, N. Gagliani, D. Gallo, J.-F. Chen, F. H. Bach, and L. E. Otterbein Cross-Regulation of Carbon Monoxide and the Adenosine A2a Receptor in Macrophages J. Immunol., May 1, 2007; 178(9): 5921 - 5929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. H. Nemeth, B. Csoka, J. Wilmanski, D. Xu, Q. Lu, C. Ledent, E. A. Deitch, P. Pacher, Z. Spolarics, and G. Hasko Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis J. Immunol., May 1, 2006; 176(9): 5616 - 5626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Roman, H. N. Rivera, S. Roser-Page, S. V. Sitaraman, and J. D. Ritzenthaler Adenosine induces fibronectin expression in lung epithelial cells: implications for airway remodeling Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L317 - L325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. H. Nemeth, C. S. Lutz, B. Csoka, E. A. Deitch, S. J. Leibovich, W. C. Gause, M. Tone, P. Pacher, E. S. Vizi, and G. Hasko Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism J. Immunol., December 15, 2005; 175(12): 8260 - 8270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Ralph, A. N. McEvoy, D. Kane, B. Bresnihan, O. FitzGerald, and E. P. Murphy Modulation of Orphan Nuclear Receptor NURR1 Expression by Methotrexate in Human Inflammatory Joint Disease Involves Adenosine A2A Receptor-Mediated Responses J. Immunol., July 1, 2005; 175(1): 555 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hakonarson, S. Thorvaldsson, A. Helgadottir, D. Gudbjartsson, F. Zink, M. Andresdottir, A. Manolescu, D. O. Arnar, K. Andersen, A. Sigurdsson, et al. Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial JAMA, May 11, 2005; 293(18): 2245 - 2256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Reece, P. I. Ellman, T. S. Maxey, I. K. Crosby, P. S. Warren, T. W. Chong, R. D. LeGallo, J. Linden, J. A. Kern, C. G. Tribble, et al. Adenosine A2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1137 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Linden Adenosine in Tissue Protection and Tissue Regeneration Mol. Pharmacol., May 1, 2005; 67(5): 1385 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Thiele, R. Kronstein, A. Wetzel, A. Gerth, K. Nieber, and S. Hauschildt Regulation of Adenosine Receptor Subtypes during Cultivation of Human Monocytes: Role of Receptors in Preventing Lipopolysaccharide-Triggered Respiratory Burst Infect. Immun., March 1, 2004; 72(3): 1349 - 1357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schnurr, T. Toy, A. Shin, G. Hartmann, S. Rothenfusser, J. Soellner, I. D. Davis, J. Cebon, and E. Maraskovsky Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells Blood, February 15, 2004; 103(4): 1391 - 1397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gomez and M. V. Sitkovsky Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo Blood, December 15, 2003; 102(13): 4472 - 4478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J F Kinsel and M V Sitkovsky Possible targeting of G protein coupled receptors to manipulate inflammation in vivo using synthetic and natural ligands Ann Rheum Dis, November 1, 2003; 62(90002): ii22 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. H. Neemeth, S. J. Leibovich, E. A. Deitch, E. S. Vizi, C. Szabo, and G. Hasko cDNA Microarray Analysis Reveals a Nuclear Factor-{kappa}B-Independent Regulation of Macrophage Function by Adenosine J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1042 - 1049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Lamendola, Z. Duan, R. Z. Yusuf, and M. V. Seiden Molecular Description of Evolving Paclitaxel Resistance in the SKOV-3 Human Ovarian Carcinoma Cell Line Cancer Res., May 1, 2003; 63(9): 2200 - 2205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mirani, I. Elenkov, S. Volpi, N. Hiroi, G. P. Chrousos, and T. Kino HIV-1 Protein Vpr Suppresses IL-12 Production from Human Monocytes by Enhancing Glucocorticoid Action: Potential Implications of Vpr Coactivator Activity for the Innate and Cellular Immunity Deficits Observed in HIV-1 Infection J. Immunol., December 1, 2002; 169(11): 6361 - 6368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bshesh, B. Zhao, D. Spight, I. Biaggioni, I. Feokistov, A. Denenberg, H. R. Wong, and T. P. Shanley The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells J. Leukoc. Biol., November 1, 2002; 72(5): 1027 - 1036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gounaris Nucleotidase Cascades Are Catalyzed by Secreted Proteins of the Parasitic Nematode Trichinella spiralis Infect. Immun., September 1, 2002; 70(9): 4917 - 4924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Okusa A2A adenosine receptor: a novel therapeutic target in renal disease Am J Physiol Renal Physiol, January 1, 2002; 282(1): F10 - F18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Khoa, M. C. Montesinos, A. B. Reiss, D. Delano, N. Awadallah, and B. N. Cronstein Inflammatory Cytokines Regulate Function and Expression of Adenosine A2A Receptors in Human Monocytic THP-1 Cells J. Immunol., October 1, 2001; 167(7): 4026 - 4032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M CUTOLO, A SULLI, C PIZZORNI, B SERIOLO, and R H STRAUB Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis Ann Rheum Dis, August 1, 2001; 60(8): 729 - 735. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Gerber and D. M. Mosser Reversing Lipopolysaccharide Toxicity by Ligating the Macrophage Fc{{gamma}} Receptors J. Immunol., June 1, 2001; 166(11): 6861 - 6868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. la Sala, D. Ferrari, S. Corinti, A. Cavani, F. Di Virgilio, and G. Girolomoni Extracellular ATP Induces a Distorted Maturation of Dendritic Cells and Inhibits Their Capacity to Initiate Th1 Responses J. Immunol., February 1, 2001; 166(3): 1611 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Elenkov, R. L. Wilder, G. P. Chrousos, and E. S. Vizi The Sympathetic Nerve---An Integrative Interface between Two Supersystems: The Brain and the Immune System Pharmacol. Rev., December 1, 2000; 52(4): 595 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
